This ViCTER is built around the currently funded project 'Environmental Arsenic and Diabetes Mellitus'(R01 ES015326-01A2, PI: Miroslav Styblo). The current R01 project (further referred to as the parent project) uses a translational approach to characterize the association between chronic exposures to arsenic (As) and diabetes mellitus. The main goals of the parent project are: (1) to identify molecular mechanisms underlying the diabetogenic effects of inorganic As (iAs), (2) to identify specific metabolites of iAs that are responsible for these effects, and (3) to characterize genetic polymorphisms and dietary habits that are associated with increased susceptibility of individuals to iAs-induced diabetes. The proposed ViCTER will expand the scope of the parent project to include a comprehensive assessment of metabolomic and epigenomic profiles associated with iAs exposure and with iAs-induced disease. The primary objectives are: (1) to examine a complete As metabolome (arsenome) in urine of mice and humans who develop diabetes as a result of exposure to iAs;(2) to characterize tissue dosimetry for key metabolites of iAs, using exfoliated human urothelial cells;(3) to identify DNA methylation, and (4) to identify general metabolomic profiles associated with iAs exposure and with iAs-induced diabetes. Results of this work will provide novel information about the metabolomic and epigenetic fingerprints that characterize both the exposure to iAs and the iAs-induced diabetes. Integration of data from mouse and human studies will help to identify specific methylation profiles for genes and gene clusters affected by iAs exposure, and the signaling and metabolic pathways associated with these gene clusters. Using data on urinary arsenome and on the metabolites of iAs in exfoliated urothelial cells (and in mouse tissues analyzed in the parent project), we will be able to identify specific As species that are responsible for the iAs-induced changes on the epigenome and metabolome levels. The proposed research will lead to a better understanding of the mechanisms underlying the adverse effects of iAs exposures and aid in the establishment of novel biomarkers to identify individuals at greatest risk for arsenic-induced diabetes in an understudied region in Mexico and in the arsenicosis-endemic areas worldwide.